J . CHEM. SOC., CHEM. COMMUN., 1982 699

A Simple Synthesis of a Basic Skeleton of Isoatisirene Hideo Nemoto,a Masami Hashimoto,” Keiichiro Fukumoto,a and Tetsuji Kametani*b a Pharmaceutical Institute, Tohoku University, Aoba yama, Sendai 980, Japan b Hoshi College of Pharmacy, Ebara 2-4-47, Shinagawa-ku, Tokyo 142, Japan

The 3-methoxy-7-methyl-4b,5,6,8a,9,1 O-hexahydro-6,8a-ethanophenanthrenes (2) and (26), potential inter- mediates for the synthesis of isoatisirene (?), have been synthesised by using an intramolecular cycloaddition reaction of the o-quinodimethan (5), which was itself derived thermally from 5-methoxy- 1 - (2- methyl -3-0x0 -4- phenylt hiomet hylenecyclo hexylmethyl) -1,2 -di hydrocyclobuta benzene (I 7).

Since the bridged bicyclo [2.2.2]octane constitutes an integral benzenes, we have investigated a facile route to the potential part of the structure of a large class of diterpenoids and intermediate ( 2 ) for the synthesis of isoatisirene (l) , since we diterpene alkaloids,lY2 many efforts have been made to had already found an efficient method for the stereoselective construct this unique ring In connection with our conversion of (3) into dihydrohibaene (4),12 which might be interestg-” in the development of synthetic cycloaddition applied to the transformation of ( 2 ) into (1) (Scheme 1). reactions of o-quinodimethans based on dihydrocyclobuta- The most challenging feature of this study is the cyclo-

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700 J . CHEM. SOC., CHEM. COMMUN., 1982

Me

Me0 Go \ - (3)

Scheme 1

0 1- . ..,

Me

(4)

H

OMe

( 5 b)

‘h

+

SPh

H

Me0 SPh .-

SPh

( 5 c ) (7) Scheme 2

addition to the o-quinodimethan (5) through a conforma- tionally unfavoured intermediate in either the e m - (5b) or endo- (5c) form, having a boat-like conformation of the cyclo- hexane ring, leading to (6) and (7) respectively; rather than the conformationally favoured intermediate (5a) which has a chair-like conformation and in which the diene and dieno- phile are too far apart to interact with each other (Scheme 2).

X SOPh

( 8 ) X = OSO,C,H,-p-Me

(9) X = SPh (11)

1 (1 0 ) X = SOPh

X

0

(14) X = H,

(15) x CHOH

( 1 6 ) X = CHOS02Me

(17) x = CHSPh

0

(12 ) X = SOPh

(13) X H

Scheme 3

The synthesis of the cyclobutabenzene (17), a source for generating the o-quinodimethan (5j, was straightforward and as follows (Scheme 3). The sulphoxide (lo), prepared in 86% overall yield from the p-toluenesulphonate ( t 3 ) 1 2 via the sulphide (9) by successive treatment with sodium thiopheno- late in dimethylformamide followed by m-chloroperbenzoic acid in CH2CI2, was condensed with 2-methylcyclohex-2- enone13 in tetrahydrofuran (THF) in the presence of lithium di-isopropylamide to give the compound (11) [m/z 382 ( M s j ] in 38% yield. The enone (13) [vmas (CHCI,) 1650 cm-l, m / z 256 (M+)], obtained in 81 % overall yield by treating (11) with pyridinium chlorochromate in CH2CI, and the resulting product (12) with zinc in AcOH, was hydrogenated in MeOH in the presence of palladium-carbon under an atmosphere of hydrogen to afford the cyclohexanone (14) [vmax (CHCI,) 1700 cm-l, m/z 258 (M+)] in 70% yield. Introduction of the dienophile moiety into the cyclohexanone (14) was carried out effectively in 60 % overall yield via the hydroxymethylene derivative (15) and the methanesulphonate (16) by successive treatment of (14) with ethyl formate in benzene in the presence of sodium hydride and then the product (15) with mesyl chloride, followed by thiophenol in pyridine furnishing the thiomethylene derivative (17) [vmax (CHC13) 1660 cm-I,

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J. CHEM. SOC., CHEM. COMMUN., 1982 70 1

8(CCl,) 1.20 (3H, d, J 8 Hz, Me), 3.66 (3H, s, OMe), 6.36- 6.90 (3H, m, ArH), and 7.30 (6H, br. s, >C=CH-S-ArH), in/z 378 ( M + ) ] .

Heating (17) in o-dichlorobenzene at 200 “C for 10 h in a current of nitrogen afforded the tetracyclic compounds (6) and (7) as an inseparable stereoisomeric mixture [vmax (CHCI,) 1705 cm-l, m / z 378 (M-I )] in 95% yield. The stereochemistry at the ring junction of (6) and (7) was easily deduced by con- verting (6) and (7) into the styrenes (20) and (21) and then into (2) and (26), respectively. Thus, oxidation of (6) and (7) with nz-chloroperbenzoic acid and then elimination of the phenyl- sulphinyl group from the resulting sulphoxides (18) and (19) gave the styrenes (20) [vmax (CHCI,) 1705 cm-I, ni/z 268 (M+)] and (21) [vmaX (CHCI,) 1705 cm-l, m/z 268 ( M i ) ] in 14% and 37 % overall yields, respectively, after purification by chromatography on silica gel [n-hexane-benzene (4 : l)]. The n.m.r. spectra of (20) and (21) could be diagnostic for the stereochemical assignment; namely, an olefinic proton at C-9 of (20), suffering from the deshielding effect of the carbonyl group, was observed at 6 6.08 as a doublet having J 10 Hz. For (21), the corresponding olefinic proton would not be expected to be deshielded by the carbonyl group and the resonances were observed at normal positions, 6 5.35 and 5.38, as doublets having J 10 H z . t

Finally, the olefinic ketones (20) and (21) were hydrogenated in methanol in the presence of palladium-carbon under an

Me

( 2 0 )

Since the methyl group at C-7 of (20) was observed at 6 1.15 and 1.26 as doublets having J 6 Hz and that of (21) at 8 0.98 and 1.10 having J 8 Hz, respectively, the compounds (20) and (21) were found to be stereoisomeric mixtures at C-7. This was confirmed by converting (20) and (21) into stereoisomerically pure (2) and (26) respectively.

atmosphere of hydrogen to give the ketones (22) and (23) in 45 % and 59 % yields, respectively, the tosylhydrazides (24) and (25) of which were subjected to the Shapiro reaction using n-butyl-lithium in THF furnishing the initial target compounds (2) [6 (CDCI,) 1.78 (3H, d, J 1.0 Hz, Me), 3.65 (3H, s, OMe), 5.6 ( lH, br. s, olefinic H), and 6.5-7.0(3H, m, ArH), m/z 254 (M+)] and (26) [6 (CDCI,) 1.70 (3H, d, J 1.0 Hz, Me), 3.76 (3H, s, OMe), 5.60 ( I H , br. s, olefinic H), and 6.42-7.0 (3H, m, ArH), m / z 254 ( M +) I .

Thus we report a simple and novel route for the synthesis of the potential intermediate (2) for preparing isoatisirene (l), and show that the stereochemical course of the cycloaddition reaction of the o-quinodimethan (5) is vicr (5b) and (5c) by overcoming the conformational disadvantage.

Received, 2i1d April 1982; Conr. 371

References 1 T. K. Devon and A. I. Scott, ‘Handbook of Naturally

Occurring Compounds,’ Vol. 11, Terpenes, Academic Pre\s, New York, 1972.

2 ‘Terpenoids and Steroids,’ ed. .I. R. Hanson (Specialist Periodical Reports), The Royal Society of Chemistry, London, V O l . 1-10.

3 R. A. Bell, R. E. Ireland, and R. A. Partyka, J . Or-g. Cht?t?1., 1966, 31, 2530.

4 S. W. Pelletier and P. C. Parthasarathy, Tetrcihrdrorr Lett., 1963, 205.

5 W. Nagata, T. Sugasawa, M. Narisada, T. Wakabayashi, and Y . Hayase, J . Am. Clzern. Soc., 1963, 85, 2332; ibid., 1967, 89, 1483.

6 T. Y. R. Tsai, C. S. J . Tsai, W. W. Sy, M. N . Shanbhag, W. C. Liu, S . F. Lee, and K. Wiesner, H e t e v a c ~ d e s , 1977, 7, 217.

7 L. H. Zalkow and N. N . Girotra, J . OrAJ. Clieiu., 1964, 29, 1299.

8 T. Kametani, T. Honda, K. Fukurnoto, M. Toyota, and M. Ihara, Heterocycles, I98 I, 16, 1673.

9 T. Kametani and K . Fukumoto, Herer-oc,des, 1975, 3, 29; ibid., 1977, 8, 465.

10 T. Kametani and H. Nemoto, Tctrriliec/r-on, 1981, 37, 3. 11 T. Kametani, K. Suziiki, and H. Nemoto, J . Am. Chenz. Soc.,

198 1 , 103, 2890. 12 T. Kametani, K. Suzuki, H. Nemoto, and K. Fukumoto,

J . Org. Chem., 1979, 44, 1036. 13 E. W. Warnhoff, D. G. Martin, and W. S. Johnson, Org.

Synrh., 1963, 4, 162.

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